1,2,3-Propanetriol, mono- and diformates

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Reference 1

Endpoint:

multi-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: secondary literature

Qualifier:

equivalent or similar to guideline

Guideline:

other: series of three multi-generation and chronic toxicity studies

Deviations:

not applicable

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: drinking water

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

throughout 5 generations over a 3-year period

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
150-200 mg/kg bw/day
Basis:
nominal in water

No. of animals per sex per dose:

8 males and 24 females

Control animals:

yes

Reproductive effects observed:

not specified

Conclusions:

In a multi-generation reproduction study calcium formate was administered to Wistar rats in drinking water at dose levels of 150-200 mg/kg bw/day throughout 5 generations over a 3 -year period. This study is not reliable due to the lack of reported data but provides information for a weight of evidence analysis.

Reference 2

Endpoint:

toxicity to reproduction

Remarks:

other: 13-week study

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP guideline study, according to and exceeding the requirements of the OECD TG 413 with additional emphasis on some of the male and female reproductive parameters. Tested with the source substance formic acid (CAS No. 64-18-6). For details on read-across refer to the attached read-across report.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD 413

Deviations:

yes

Remarks:

emphasis on some of the male and female reproductive parameters including sperm morphology and vaginal cytology

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Exposure period: 13 weeks

Frequency of treatment:

5 days/week, 6 h/day

Remarks:

Doses / Concentrations:
0; 8; 16; 32; 64; 128 ppm (as vapour)
Basis:

Remarks:

Doses / Concentrations:
0; 0.015; 0.031; 0.120; 0.241 mg/m3
Basis:

No. of animals per sex per dose:

10/sex/group

Control animals:

yes

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes

Oestrous cyclicity (parental animals):

oestrus cyclicity analysed in rats of the 0, 8, 32, 128 ppm groups

Sperm parameters (parental animals):

sperm motility and concentration were analysed in rats of the 0, 8, 32, 128 ppm groups

Postmortem examinations (offspring):

At sacrifice, among other organs, the right testis was weighed

Clinical signs:

not specified

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

not examined

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): body weight gains of the male rats of the 8, 16, 32 and 64 ppm groups
were slightly increased as compared to the control rats

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): no effects observed

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): no effects were observed on testicular weight, epididymal weight, sperm motility and epididymal and testicular sperm concentration

Dose descriptor:

NOAEL

Effect level:

0.244 mg/L air

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Reproductive effects observed:

not specified

Result: no effects on sperm motility, density, and testes and epididymal weight,  or estrous cycle length
RS-Freetext:
Male and female reproductive organs: 
Regarding the male and female reproductive organs, there
were no effects on sperm motility, density or testicular or
epididymal weights, and no changes were seen in the length
of the estrous cycle at any dose.

===========================================================
Parameter          Exposure concentration (ppm)   
                    0         8         32          128
-----------------------------------------------------------
Males
Weight (g)
right testis      1.40      1.45       1.47       1.41
left epididymis   0.449     0.461      0.469      0.460   
left epididymal   0.167     0.171      0.174      0.169
tail

Spermatozoal measurements
Motility (%)     91+/-1     91+/-1     91+/-1     88+/-1
Concentration   658+/-21   706+/-21   580+/-60   651+/-29  
(10E06/g)


Females
Estrous cycle    4.80       4.75       4.95        4.95
length (d)       
===========================================================

The NOAEC was therefore 0.244 mg/l for systemic toxicity and
effects ob reproductive organs, and 0.122 mg/l for local
irritation in the respiratory tract.

Conclusions:

Formic acid does not have adverse effects on F344 male and female rats when exposed via inhalation to concentrations up to 128 ppm.

Executive summary:

In a reproduction study, formic acid was administered to 10 F344 rats/sex/dose via inhalation at dose levels of 0, 8, 16, 32, 64, and 128 ppm (0, 15, 30, 120, or 240 mg/kg bw/day).  

No effects were observed on oestrus cyclicity, testicular weight, epididymal weight, sperm motility and epididymal and testicular sperm concentration. Body weight gains of the male rats of the 8, 16, 32 and 64 ppm groups were slightly increased as compared to the control rats. The NOAEL is 0.244 mg/L air in males and females.  

This study is acceptable and satisfies the guideline requirement for a 90-daysubchronic inhalation toxicity test to examine reproductive endpoints; OECD 413, in rodents.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

400 mg/kg bw/day

Study duration:

chronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

244 mg/m³

Study duration:

subchronic

Species:

rat

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The hazard assessment of 1,2,3-propanetriol, mono- and diformates is based on its degradation products glycerol and formic acid/formates. In a 13 week inhalatory toxicity study, F344/N rats (10/sex/group) and B6C3F1 mice (10/sex/group) were exposed to formic acid (0, 8, 16, 32, 64 and 128 ppm) for 6 h/day, 5 days/week. Sperm motility and concentration and oestrus cyclicity were analysed in rats and mice of the 0, 8, 32 and 128 ppm groups. At sacrifice, among other organs, the right testis was weighed. In the 128 ppm group two mice died. In rats, body weight gains of the male rats of the 8, 16, 32 and 64 ppm groups were slightly increased as compared to the control rats. In mice, body weight gains were significantly decreased in mice exposed to 64 and 128 ppm formic acid. In both species, no effects were observed on oestrus cyclicity, testicular weight, epididymal weight, sperm motility and epididymal and testicular sperm concentration.

The oral toxicity of two formates in Wistar rats was investigated in a series of three poorly reported multi-generation and chronic toxicity studies by Malorny. In the first study, 8 males and 24 females were given 0.2% calcium formate in drinking water (150-200 mg calcium formate/kg body weight/day) and a control group of 8 animals, sex not specified, was used. The exposure was continued with the offspring of the original rats, throughout 5 generations over a 3-year period. In a second study, rats were given 0.4% calcium formate (300-400 mg/kg body weight/day) for up to 2 years (2 generations) at the date of publication. No treatment-related effects were observed on body weight (gain) and macroscopic and histopathological examination of lung, spleen, stomach, liver, kidneys, and other, not specified, organs. No effects were observed on reproduction (as presented by numbers of offspring). Malorny described another multi-generation and chronic study with Wistar rats (n=6/group) given 1% sodium formate in drinking water for, at the time of the publication, 1.5 years but no details of this study were described concerning toxicity of the compound. In addition, no adverse effects to reproduction have been reported for glycerol when administered via drinking water to rats at doses up to 2000 mg/ kg bw/day for 2 generations.

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Low number of experimental animals per dose group, only one dose level has bee tested, and not all examination parameters of an OECD 414 study were fulfilled.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

CD-1

Route of administration:

oral: gavage

Vehicle:

not specified

Duration of treatment / exposure:

mice were given a single dose of sodium formate on day 8 of gestation

Frequency of treatment:

once

Duration of test:

dams were sacraficed on day 10 or 18 of gestation

Remarks:

Doses / Concentrations:
0, 750 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

n=10-14

Control animals:

yes

Dose descriptor:

NOAEL

Effect level:

750 mg/kg bw (total dose)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

The incidence of neural tube defects was not affected by sodium formate up do a dose of 750 mg/kg bw on day 8 of gestation in CD-1 mice

Executive summary:

In a developmental toxicity study sodium formate was administered to 10-14 female CD-1 mice by oral gavage at dose levels of 0 or 750 mg/kg bw on day 8 of gestation.

The incidence of neural tube defects was not affected by sodium formate. The developmental NOAEL is 750 mg/kg bw, the highest dose administered.  

The developmental toxicity study in the mouse is classified as acceptable, and satisfies the main guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rodents.  Major deficiencies include a low number of experimental animals per dose group, testing only one dose level, and not all examination parameters were fulfilled.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

750 mg/kg bw/day

Study duration:

subacute

Species:

mouse

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In a single dose study (Dorman, 1995) no effect of sodium formate on the incidence of neural tube defects was observed in mice. In the same study, the incidence of neural tube effects following administration of methanol was statistically significantly increased. Because the formate levels in the plasma of rats given sodium formate or methanol were similar, the developmental effects induced by methanol are problably a direct effect of methanol rather than effects due to formates. In a series of poorly reported multi-generation studies described by Malorny, no effect of calcium formate given in the drinking water to Wistar rats was observed on development (as presented by weight and length of the offspring). Furthermore, no effect of sodium formate on the development of chicken embryos was observed. In several in vitro studies, the effects of formic acid and sodium formate on rat and mouse embryos was determined. In general, both formic acid and sodium formate inhibited the growth and development of the

embryos and increased the incidence of abnormalities and lethality. Both the acidity of the culture medium independently, and the concentration of formate in the culture medium appeared to contribute to the embryotoxicity of formic acid. However, because of the high reactivity of formic acid, it is not expected that a well performed developmental study would show specific developmental effects of formic acid. This is in line with the recent assessment by the Health Council of the Netherlands in 2006.

Justification for classification or non-classification

Based on the assessment of degradation products, 1,2,3-propanetriol, mono- and diforamtes does not meet the classification criteria according to Regulation (EC) 1272/2008 or according to Directive 67/548/EEC.